A kind of synthetic method of epinastine hydrochloride

A technology of epilastine hydrochloride and a synthesis method, which is applied in the field of chemical substance synthesis, and can solve problems such as difficulty in obtaining starting materials, unfavorable industrial production, high price and the like

Active Publication Date: 2019-07-02
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The synthetic starting material of this route is not easy to obtain, the price is expensive, the time required for the synthesis is 7 days, and the reaction time is extremely long, which is not conducive to industrial production

Method used

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  • A kind of synthetic method of epinastine hydrochloride
  • A kind of synthetic method of epinastine hydrochloride
  • A kind of synthetic method of epinastine hydrochloride

Examples

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Effect test

Embodiment 1

[0094] A method for synthesizing epinastine hydrochloride, including the following steps: mixing tert-butoxycarbonyl protected substance B with dichloromethane, adjusting the temperature to 15°C, adding dicyclohexylcarbodiimide, and stirring for 0.5h, Then add the substance A dichloromethane solution dropwise, keep stirring for 12h, add water, 3wt% potassium carbonate aqueous solution and saturated sodium chloride aqueous solution in turn, and wash once. Take the organic layer for each extraction and then concentrate under reduced pressure. Drying to obtain substance C, wherein the molar ratio of substance A to substance B is 1:1.2, and the weight ratio of substance B to dicyclohexylcarbodiimide is 1:1;

[0095] Mix substance C with polyphosphoric acid, heat to 120°C, keep stirring for 2h, add dichloromethane to extract the organic layer, wash the organic layer with water, 3wt% potassium carbonate aqueous solution and saturated sodium chloride aqueous solution successively, reduce...

Embodiment 2

[0099] A method for synthesizing epinastine hydrochloride, including the following steps: mix benzyl protected substance B with ethyl acetate, adjust the temperature to 35°C, add 4,5-dicyanoimidazole, stir for 1 hour, and then drop Add substance A ethyl acetate solution, keep warm and stir for 2h, add water, mass fraction of 7wt% sodium carbonate aqueous solution, saturated sodium chloride aqueous solution each extraction and wash once, take the organic layer for each extraction, then concentrate under reduced pressure and dry Obtain substance C, wherein the molar ratio of substance A to substance B is 1:1, and the weight ratio of substance B to 4,5-dicyanoimidazole is 1:1.2;

[0100] Mix substance C with polyphosphoric acid, heat to 160°C, keep stirring for 0.5h, add ethyl acetate to extract the organic layer, wash the organic layer with water, 7wt% sodium carbonate aqueous solution and saturated sodium chloride aqueous solution in turn, Concentrate under reduced pressure and dr...

Embodiment 3

[0104] A method for synthesizing epinastine hydrochloride, comprising the following steps: mixing the benzyloxycarbonyl protected substance B with dichloromethane, adjusting the temperature to 20°C, adding N,N-carbonyl-diimidazole, and stirring for 0.6h, Then add dropwise the 1,2-dichloroethane solution of substance A, keep it warm and stir for 10 hours, add water, 4wt% sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution successively and wash once, each extraction washes organic Layer, then concentrated under reduced pressure and dried to obtain substance C, wherein the molar ratio of substance A to substance B is 1:1.18, and the weight ratio of substance B to N,N-carbonyl-diimidazole is 1:1.13;

[0105] Mix substance C with polyphosphoric acid, heat to 130°C, keep stirring for 1.5h, add dichloromethane to extract the organic layer, and wash the organic layer with water, 4wt% sodium hydroxide aqueous solution and saturated sodium chloride aqueous solut...

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Abstract

The invention discloses a synthetic method of epinastine hydrochloride. The synthetic method comprises the following steps: enabling a substance A to react with a substance B to obtain a substance C; enabling the substance C to be subjected to ring closing reaction with polyphosphoric acid to obtain a substance D; enabling the substance D to react with a de-protection reagent to obtain a substance E; enabling the substance E to react with cyanogen bromide to obtain epinastine and then salifying with hydrochloric acids to obtain the epinastine hydrochloride. The synthetic method disclosed by the invention is easily-available in raw materials, mild in reaction conditions, low in energy consumption, low in production cost, simple to operate, short in preparation period and suitable for large-scale industrial production; the prepared epinastine hydrochloride is high in purity and relatively high in yield in each step of reaction.

Description

Technical field [0001] The invention relates to the technical field of chemical substance synthesis, in particular to a method for synthesizing epinastine hydrochloride. Background technique [0002] Epinastine hydrochloride, whose chemical name is 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azahydrochloride, The molecular formula is C 16 H 15 N 3 ·HCl, its chemical structure is as follows: [0003] [0004] Epistin hydrochloride is an effective oral antihistamine developed by Boehringer Ingelheim, Germany. It cooperated with Sankyo Pharmaceuticals of Japan to further develop the market. It was first listed in Japan in 1994 under the trade name "Alesion". Epistin hydrochloride is used to treat bronchial asthma, allergic dermatitis, urticaria, eczema, dermatitis and common psoriasis (psoriasis). It has a strong inhibitory effect on bronchoconstriction caused by histamine and bradykinin. It has no inhibitory effect on bronchoconstriction caused by other chemical media. It is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 高永好陈仕云何勇彭扶云吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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